title: Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.
abstract: Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, California 92130, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Dyck
authors.forename: Junko
authors.initials: J
authors.lastname: Tamiya
authors.forename: Florence
authors.initials: F
authors.lastname: Jovic
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Pick
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Bradbury
authors.forename: Julie
authors.initials: J
authors.lastname: O'Brien
authors.forename: Jenny
authors.initials: J
authors.lastname: Wen
authors.forename: Michael
authors.initials: M
authors.lastname: Johns
authors.forename: Ajay
authors.initials: A
authors.lastname: Madan
authors.forename: Beth A
authors.initials: BA
authors.lastname: Fleck
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.forename: Binfeng
authors.initials: B
authors.lastname: Li
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Zhang
authors.forename: Joe A
authors.initials: JA
authors.lastname: Tran
authors.forename: Troy
authors.initials: T
authors.lastname: Vickers
authors.forename: Jonathan
authors.initials: J
authors.lastname: Grey
authors.forename: John
authors.initials: J
authors.lastname: Saunders
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D003521:Cyclopropanes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D000078764:Milnacipran; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D009437:Neuralgia / Q000188:drug therapy* / Q000473:pathology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013127:Spinal Nerves / Q000473:pathology / Q000601:surgery; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D000078764:Milnacipran; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors